This project consists of two related lines of research evaluating 1) the neuroendocrine responses to surgical stress and inflammatory pain, as evidenced by measuring changes in circulating beta-endorphin (B-END) and bradykinin (BK), 2) the analgesic effects of prototypic and novel drugs as indicated by both behavioral effects and alterations in the activity of these substances. Stimulation of the pituitary-adrenal axis by corticotropin releasing factor (CRF) suppresses clinical post-operative pain, while inhibition of the axis by dexamethasone enhances post-operative pain. When further evaluated in animals, CRF analgesia is demonstrated to be due to secretion of pituitary B-END. Separate animal studies evaluated neuroendocrine responses to inflammation. Circulating levels of both BK and B-END significantly increase during inflammation. The hypothesis that blood-borne BK stimulates pituitary secretion of B-END is indirectly supported by observations that 1) injections of BK into anesthetized rats stimulates secretion of B-END, and 2) that BK administered to pituitary cultures in vitro stimulates B-END secretion. Studies currently underway directly test this hypothesis. In addition, inhibition of BK synthesis blocks the development of inflammatory hyperalgesia in rats. Increased knowledge into the neuroendocrine responses to inflammatory pain should provide a logical avenue for the development of new types of analgesic drugs.